Salmonellosis continues to be a major Public Health concern. The pathogenicity of Salmonella enterica requires the activity of two type III protein secretion systems (T3SS) encoded within its pathogenicity islands 1 and 2. These T3SSs direct the translocation into host cells of a battery of bacterial effector proteins, which working in conjunction with one another, modulate a variety of cellular processes including actin cytoskeleton dynamics, gene expression, vesicle trafficking, and programmed cell death. Modulation of these cellular activities allows Salmonella to gain access to and replicate within host cells, avoid host defense mechanisms, induce intestinal inflammation, and/or reach deeper tissues. Over the years, work in our laboratory supported by this Grant has focused on the study of the cell biology of the complex functional interface between Salmonella enterica serovar Typhimurium (S. Typhimurium) and its host cells shaped by the activities of T3SS effector proteins. During the last funding period we have made significant progress in the understanding of the structure and function of several Salmonella T3SS effector proteins, as well as on the cellular responses that they elicit. Despite this progress, the biochemical activities and/or cellular targets of the majority of these effector proteins remain uncharacterized. During the next funding period we plan to use a multidisciplinary approach to study S. Typhimurium effector proteins, identified their cellular targets and examine their contribution to the host/pathogen interactions.